Fluorinated 2-amino-4-(benzylamino)phenylcarbamate derivatives

ABSTRACT

The invention relates to fluorinated compounds and their use as anti-epileptic, muscle-relaxing, fever-reducing and peripherally analgesically acting medications and as imaging agents. Novel fluorinated 2-amino-4-(benzylamino)phenyl carbamate derivatives of ezogabine and pharmaceutically acceptable salts or solvates thereof and their use are described.

RELATED APPLICATION

This application claims priority under 35 U.S.C. §119(e) to U.S.provisional application Nos. 61/640,157 and 61/697,690, respectivelyfiled on Apr. 30, 2012 and Sep. 6, 2012, which are incorporated hereinby reference.

BACKGROUND

Epilepsy is one of the most common chronic neurological disorders. It iscommonly diagnosed after 2 or more unprovoked seizures separated by atleast 1 day, and it affects approximately 50 million people worldwide.Epilepsy is a serious and potentially life threatening disease andpatients with epilepsy have significantly increased morbidity, includingclosed head injury, fractures, burns, dental injury and soft tissueinjury. Decline in or worsening of memory, cognition, depression andsexual function and other lifestyle limitations occur frequently inpatients with epilepsy. Patients with epilepsy also have an increasedrisk of mortality compared to the general population.

Despite the fact that there are already approved pharmacologic agents totreat epilepsy, many patients are not adequately treated with currentlyavailable options. It is estimated that nearly a third of patients withepilepsy have either intractable or uncontrolled seizures or havesignificant adverse side effects secondary to medication limiting theirability to appropriately control their epilepsy with medication.

Ezogabine or retigabine, also known as ethylN-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate is ananticonvulsant used as a treatment for partial epilepsies. Ezogabineworks primarily as a potassium channel opener—that is, by activatingKCNQ2/3 voltage-gated potassium channels in the brain. Ezogabine wasapproved by the FDA on Jun. 10, 2010 and is marketed as Potiga™ andTrobalt™. U.S. Pat. No. 5,384,330 and WO 01/01970 describe ezogabine andits use. The most common adverse events with ezogabine are centralnervous system effects, particularly dizziness and somnolence. Theseside effects are typical for antiepileptic drugs. Occasional instancesof urinary difficulty may require surveillance. Ezogabine ispredominantly metabolized via glucuronidation. Its half-life is 8 hours.

Despite the beneficial activities of ezogabine, there is a continuingneed for new compounds to treat epilepsy and other conditionsameliorated by KCNQ2/3 potassium channel opening.

Fluorine-18 compounds that bind to KCNQ2/3 voltage-gated potassiumchannels are also needed to non-invasively determine the functionalstatus of the channels by positron emission tomograghy (PET). PETimaging of subjects suffering from epilepsy or other conditionsameliorated by KCNQ2/3 potassium channel opening may provide clinicallyimportant information related to diagnosis of the condition,appropriateness and dosing of treatment, as well as facilitating theclinical development of new treatments.

DETAILED DESCRIPTION OF THE INVENTION

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

The term “a compound of the invention” or “compounds of the invention”refers to a compound(s) disclosed herein e.g., a compound(s) of theinvention includes a compound(s) of any of the formulae described hereinincluding formulae A, I, II, III, or IV and/or a compound(s) explicitlydisclosed herein. Whenever the term is used in the context of thepresent invention it is to be understood that the reference is beingmade to the free base, a deuterium labeled compound, and thecorresponding pharmaceutically acceptable salts or solvates thereof,provided that such is possible and/or appropriate under thecircumstances. The fluorine atom or atoms in the compounds of theinvention are non-radioactive.

The term “an 18F compound of the invention” or “18F compounds of theinvention” refers to a compound(s) disclosed herein e.g., an 18Fcompound(s) of the invention includes an 18F compound(s) of any of theformulae described herein including formulae V, VI, VII, VIII, or IXand/or an 18F compound(s) explicitly disclosed herein. Whenever the termis used in the context of the present invention it is to be understoodthat the reference is being made to the free base and the correspondingpharmaceutically acceptable salts thereof, provided that such ispossible and/or appropriate under the circumstances. For 18F compoundsof the invention that also comprise non-radioactive fluorine, thenon-radioactive fluorine is designated as 19F.

The term “pharmaceutical” or “pharmaceutically acceptable” when usedherein as an adjective, means substantially non-toxic and substantiallynon-deleterious to the recipient.

By “pharmaceutical formulation” it is further meant that the carrier,solvent, excipient(s) and salt must be compatible with the activeingredient of the formulation (e.g. a compound of the invention). It isunderstood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

Some of the compounds of the present invention may exist in unsolvatedas well as solvated forms such as, for example, hydrates.

“Solvate” means a solvent addition form that contains either astoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate. In the hydrates, the water moleculesare attached through secondary valencies by intermolecular forces, inparticular hydrogen bridges. Solid hydrates contain water as so-calledcrystal water in stoichiometric ratios, where the water molecules do nothave to be equivalent with respect to their binding state. Examples ofhydrates are sesquihydrates, monohydrates, dihydrates or trihydrates.Equally suitable are the hydrates of salts of the compounds of theinvention

The invention also includes metabolites of the compounds describedherein.

Physiologically acceptable, i.e. pharmaceutically compatible, salts canbe salts of the compounds of the invention with inorganic or organicacids. Preference is given to salts with inorganic acids, such as, forexample, hydrochloric acid, hydrobromic acid, phosphoric acid orsulphuric acid, or to salts with organic carboxylic or sulphonic acids,such as, for example, acetic acid, trifluoroacetic acid, propionic acid,maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonicacid, benzenesulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

Other pharmaceutically compatible salts which may be mentioned are saltswith customary bases, such as, for example, alkali metal salts (forexample sodium or potassium salts), alkaline earth metal salts (forexample calcium or magnesium salts) or ammonium salts, derived fromammonia or organic amines, such as, for example, diethylamine,triethylamine, ethyldiisopropylamine, procaine, dibenzylamine,N-methylmorpholine, dihydroabietylamine or methylpiperidine.

As used herein, the term “treat,” “treating,” or “treatment” herein, ismeant decreasing the symptoms, markers, and/or any negative effects of adisease, disorder or condition in any appreciable degree in a patientwho currently has the condition. The term “treat”, “treating”, or“treatment” includes alleviating symptoms of a disease, disorder, orcondition e.g., alleviating the symptoms of epilepsy. In someembodiments, treatment may be administered to a subject who exhibitsonly early signs of the condition for the purpose of decreasing the riskof developing the disease, disorder, and/or condition.

As used herein, the term “prevent,” “prevention,” or “preventing” refersto any method to partially or completely prevent or delay the onset ofone or more symptoms or features of a disease, disorder, and/orcondition. Prevention may be administered to a subject who does notexhibit signs of a disease, disorder, and/or condition.

As used herein, “subject” means a human or animal (in the case of ananimal, more typically a mammal). In one aspect, the subject is a human.In one aspect, the subject is a male. In one aspect, the subject is afemale.

As used herein, the term a “fluorinated derivative” is a derivativecompound that the same chemical structure as the original compound,except that at least one atom is replaced with a fluorine atom or with agroup of atoms containing at least one fluorine atom.

The problem to be solved by the present invention is the identificationof novel compounds for the treatment and/or prevention of epilepsyand/or other conditions ameliorated by KCNQ2/3 potassium channelopening. Although drugs for epilepsy and related disorders areavailable, these drugs are often not suitable for many patients for avariety of reasons. Many epilepsy drugs are associated with adverseeffects. For example, many of the available epilepsy drugs are believedto significantly increase the risk of birth defects if taken during thefirst trimester of pregnancy. Other adverse side effects include urinaryretention, neuro-psychiatric symptoms including hallucinations andpsychosis, dizziness and somnolence, QT-prolonging effect, and increasedrisk of suicidal behavior and ideation. Some epilepsy drugs requireadministration of high doses due to extensive metabolism into inactiveor less potent metabolites.

The present invention provides the solution of new fluorinated2-amino-4-(benzylamino)phenylcarbamate compounds for treating epilepsyand other conditions ameliorated by KCNQ2/3 potassium channel opening.The fluorinated compounds described herein have the advantage ofproviding improved potency, selectivity, tissue penetration, half-life,and/or metabolic stability.

The invention also provides 18F compounds useful in methods of imaging asubject to diagnose the presence, extent, or response to therapy of adisease process. The compounds of the present invention bind with highaffinity as positive allosteric modulators of neuronal potassiumchannels, KCNQ2/3. Imaging the distribution of F-19 compound of thepresent invention can be performed by either making its F-18 congener orby a displacement or blocking experiment in the effect of administeringa KCNQ2/3 channel opener is seen by the resulting change in the image ofa F-18 KCNQ2/3 channel opener. While the correlation of the ability of aKCNQ2/3 channel opener to bind to the positive allosteric site or thespatial distribution of KCNQ2/3 channels with a particular diseaseprocess, such as epilepsy, or propensity for that disease occurring in apatient is not currently known, having a non-invasive imaging tool mayaid in determining any correlation. There are currently no known F-18labeled KCNQ2/3 channel openers.

Compounds of the Invention

The present invention relates to novel fluorinated2-amino-4-(benzylamino)phenylcarbamate derivatives and their use. Thepresent invention also relates to novel 18F-containing2-amino-4-(benzylamino)phenylcarbamate derivatives, ethyl{2-amino-6-[(benzyl)amino]pyridin-3-yl}carbamate derivatives and theiruse. The present invention relates the synthesis of fluorinated2-amino-4-(benzylamino)phenylcarbamatederivatives. The present inventionalso relates the synthesis of 18F-containing2-amino-4-(benzylamino)phenylcarbamate derivatives, and ethyl{2-amino-6-[(benzyl)amino]pyridin-3-yl}carbamate derivatives.

The invention provides a compound of formula A:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₁,X₂, X₃, X₄, X₅, X₆, X₇, and X₈ are each independently selected fromhydrogen, deuterium, and F;

-   X₉ and X₁₀ are each independently selected from hydrogen and    deuterium;-   n is 1, 2, or 3; provided that when X₆ is F, then X₁, X₂, X₃, X₄,    X₅, X₇ and X₈ are not all hydrogen. In one aspect, the invention    provides a compound of formula A, provided that the compound has at    least one fluorine atom.

While all of the compounds of this invention are useful, certain classesare preferred. The following paragraphs describe certain preferredclasses of a compound of formula A, wherein:

-   a-a) at least one of X₁, X₂, X₃, X₄, X₅, X₆, X₇ and X₈ is F;-   b-a) one of X₁, X₂, X₃, X₄, X₅, X₇ and X₈ is F;-   c-a) two of X₁, X₂, X₃, X₄, X₅, X₆, X₇ and X₈ are F;-   d-a) three of X₁, X₂, X₃, X₄, X₅, X₆, X₇ and X₈ are F;-   e-a) the remaining X₁, X₂, X₃, X₄, X₅, X₆, X₇ and/or X₈ are each    hydrogen;-   f-a) one or more of the remaining X₁, X₂, X₃, X₄, X₅, X₆, X₇ and/or    X₈ are deuterium;-   g-a) X₁₀ and X₉ are deuterium;-   h-a) n is 1;-   i-a) n is 2; and-   j-a) X₁₀ and X₉ are hydrogen.

The invention provides a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₁,X₂, X₃, X₄, X₅, X₆, X₇ and X₈ are each independently selected fromhydrogen, deuterium, and F, provided that when X₆ is F, then X₁, X₂, X₃,X₄, X₅, X₇ and X₈ are not all hydrogen. In one aspect, the inventionprovides a compound of formula I, provided that the compound has atleast one fluorine atom.

While all of the compounds of this invention are useful, certain classesare preferred. The following paragraphs describe certain preferredclasses of a compound of formula I, wherein:

-   a) at least one of X₁, X₂, X₃, X₄, X₅, X₆, X₇ and X₈ is F;-   b) one of X₁, X₂, X₃, X₄, X₅, X₇ and X₈ is F;-   c) two of X₁, X₂, X₃, X₄, X₅, X₆, X₇ and X₈ are F;-   d) three of X₁, X₂, X₃, X₄, X₅, X₆, X₇ and X₈ are F;-   e) the remaining X₁, X₂, X₃, X₄, X₅, X₆, X₇ and/or X₈ are each    hydrogen; and-   f) one or more of the remaining X₁, X₂, X₃, X₄, X₅, X₆, X₇ and/or X₈    are deuterium.

In one aspect, the invention provides a compound of formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₁,X₂, X₃, X₄, X₅, X₇ and X₈ are each independently selected from hydrogen,deuterium, and F, provided that X₁, X₂, X₃, X₄, X₅, X₇ and X₈ are notall hydrogen.

The following paragraphs describe certain preferred classes of acompound of formula II, wherein:

-   a-1) at least one of X₁, X₂, X₃, X₄, X₅, X₇ and X₈ is fluorine;-   b-1) one of X₁, X₂, X₃, X₄, X₅, X₇ and X₈ is fluorine;-   c-1) two of X₁, X₂, X₃, X₄, X₅, X₇ and X₈ are fluorine;-   d-1) the remaining X₁, X₂, X₃, X₄, X₅, X₇ and/or X₈ are each    hydrogen; and-   e-1) one or more of the remaining X₁, X₂, X₃, X₄, X₅, X₇ and/or X₈    are deuterium.

In one aspect, the invention provides a compound of formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₄,X₅, X₆, X₇ and X₈ are each independently selected from hydrogen,deuterium, and F, provided that when X₆ is F, then X₄, X₅, X₇ and X₈ arenot all hydrogen.

The following paragraphs describe certain preferred classes of acompound of formula III, wherein:

-   a-2) at least one of X₄, X₅, X₇ and X₈ is fluorine;-   b-2) one of X₄, X₅, X₇ and X₈ is fluorine;-   c-2) two of X₄, X₅, X₆, X₇ and X₈ are fluorine;-   d-2) X₄ is fluorine;-   e-2) X₅ is fluorine;-   f-2) X₇ is fluorine;-   g-2) X₈ is fluorine;-   h-2) the remaining X₄, X₅, X₆, X₇ and/or X₈ are each hydrogen; and-   i-2) one or more of the remaining X₄, X₅, X₆, X₇ and/or X₈ are    deuterium.

In one aspect, the invention provides a compound of formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein X₁,X₂, X₃, and X₆ are each independently selected from hydrogen, deuterium,and F, provided that when X₆ is F, then X₁, X₂, and X₃ are not allhydrogen. In one aspect, the invention provides a compound of formulaIV, provided that the compound has at least one fluorine atom.

The following paragraphs describe certain preferred classes of acompound of formula IV, wherein:

-   a-3) one of X₁, X₂, and X₃ is fluorine;-   b-3) one of X₁, X₂, and X₃ is fluorine;-   c-3) two of X₁, X₂, and X₃ are fluorine;-   d-3) X₁ is fluorine;-   e-3) X₂ is fluorine;-   f-3) X₃ is fluorine;-   g-3) X₆ is fluorine and one of X₁, X₂, and X₃ is fluorine;-   h-3) X₆ is hydrogen and at least one of X₁, X₂, and X₃ is fluorine;-   i-3) X₂ and X₃ are fluorine;-   j-3) the remaining X₁, X₂, and/or X₃ are each hydrogen; and-   k-3) one or more of the remaining X₁, X₂, and/or X₃ are deuterium.

It will be understood that the above classes may be combined to formadditional classes, as for example the combination of selections for twoor more substituents.

For example, for formula A, class e-a) can be combined with one ofclasses a-a), b-a), c-a), or d-a);

-   For formula A, class e-a) can be combined with one of classes a-a),    b-a), c-a), or d-a) and further combined with class j-a) and class    h-a);-   For formula A, class e-a) can be combined with one of classes a-a),    b-a), c-a), or d-a) and further combined with class j-a) and class    i-a);-   For formula A, class f-a) can be combined with one of classes a-a),    b-a), c-a), or d-a);-   For formula A, class f-a) can be combined with one of classes a-a),    b-a), c-a), or d-a) and further combined with class g-a) and class    h-a);-   For formula A, class f-a) can be combined with one of classes a-a),    b-a), c-a), or d-a) and further combined with class g-a) and class    i-a);-   For formula I, class e) can be combined with one of classes a), b),    c), or d); For formula I, class f) can be combined with one of    classes a), b), c), or d);

For formula II, class d-1) can be combined with one of classes a-1),b-1), or c-1);

-   For formula II, class e-1) can be combined with one of classes a-1),    b-1), or c-1);-   For formula III, class h-2) can be combined with one of classes    a-2), b-2), c-2), d-2), e-2), f-2), or g-2);-   For formula III, class i-2) can be combined with one of classes    a-2), b-2), c-2), d-2), e-2), f-2), or g-2);-   For formula IV, class j-3) can combined with one of classes a-3),    b-3), c-3), d-3), e-3), f-3), g-3), h-3), or i-3); and-   For formula IV, class k-3) can combined with one of classes a-3),    b-3), c-3), d-3), e-3), f-3), g-3), h-3), or i-3).

In one aspect, the invention provides a compound of Table 1.

TABLE 1 Compound # Chemical Structure 1A

2A

3A

4A

In one aspect, a compound of the invention is a pharmaceuticallyacceptable salt. In one aspect, a compound of the invention is asolvate. In one aspect, a compound of the invention is a hydrate.

The present invention relates to pharmaceutical compositions comprisingone of the compounds of the invention as an active ingredient. In oneaspect, the invention provides a pharmaceutical composition comprisingat least one compound of formulae A, I, II, III, or IV or apharmaceutically acceptable salt or solvate thereof and one or morepharmaceutically acceptable carrier or excipient. In one aspect, theinvention provides a pharmaceutical composition comprising at least onecompound of Table 1.

The present invention relates to a method of synthesizing a compound ofthe invention or a pharmaceutically acceptable salt or solvate thereof.A compound of the invention can be synthesized using a variety ofmethods known in the art. The schemes and description below depictgeneral routes for the preparation of a compound of the invention. Thesteps described herein involving nitro group reduction,benzylalkylation, and conversion of an aromatic amine to a carbamate canbe carried out in different sequences. For example, Schemes 1A and 2Adepict two possible preparations.

Schemes 1A and 2A outline preparations for a compound of the inventionof Formula A. It is understood that Formulae I, II, III, and IVdescribed herein are subsets of Formula A. Thus, the preparationsdescribed for a compound of Formula A can also be applied for thepreparation of a compound of Formulae I, II, III, and/or IV.

The preparations outlined in Schemes 1A and 2A begin with Compounds A orE. Both of which are commercially available from chemical vendors.

In Step 1 of Scheme 1A, the fluorine atom which is adjacent to the nitrogroup of Compound A is converted to an amino group to form Compound B.For example, Compound A can be treated with methanolic ammonia to formCompound B. In Step 2, the remaining fluorine atom is coupled to abenzyl amino compound to form Compound C. For example, the fluorine atomof Compound B can be coupled to 4-fluorobenzylamine using Et₃N, I₂, andDMSO to form Compound C. In Step 3, the nitro group of Compound C isreduced and a carbamate is formed to provide a compound of Formula I.For example, the nitro group of Compound C can be reduced using zincpowder and ammonium chloride in methanol. Formation of the carbamate canbe carried out using ethyl chloroformate. In some cases, Compounds B arecommercially available in which case the synthesis scheme begins at Step2.

In Step 1 of Scheme 2A, the amino group of Compound E is converted to aN,N-bis-alkoxycarbonyl group to form Compound F. For example, Compound Ecan be treated with ethyl chloroformate to form Compound F. In Step 2,the bromine atom of Compound F is coupled to a benzyl amino compound,and the N,N-bis-alkoxycarbonyl group is converted to a carbamate to formCompound G. For example, the bromine atom of Compound F can be coupledto 4-fluorobenzylamine and the N,N-bis-alkoxycarbonyl group can beconverted to an ethyl carbamate using Cs₂CO₃, Pd₂(dba)₃, and Xantphos asreagents to form Compound G. In Step 3, the nitro group is reduced to anamino group to provide a compound of Formula A. For example, the nitrogroup of Compound G can be reduced using zinc powder and ammoniumchloride in methanol.

The present invention also comprehends deuterium labeled compounds,wherein one or more hydrogen atoms is replaced by a deuterium atomhaving an abundance of deuterium at that position that is substantiallygreater than the natural abundance of deuterium, which is 0.015%. Thepresent invention comprehends deuterium labeled compounds where theethyl carbamate is deuterated e.g., compound 10A described herein.

The term “deuterium enrichment factor” as used herein means the ratiobetween the deuterium abundance and the natural abundance of adeuterium. In one aspect, a compound of the invention has a deuteriumenrichment factor for each deuterium atom of at least 3500 (52.5%deuterium incorporation at each deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium), at least 5500 (82.5% deuteriumincorporation), at least 6000 (90% deuterium incorporation), at least6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuteriumincorporation), at least 6600 (99% deuterium incorporation), or at least6633.3 (99.5% deuterium incorporation).

Deuterium labeled compounds can be prepared using any of a variety ofart-recognized techniques. For example, deuterium labeled compounds offormula I, II, III, IV, V, VI, VII, VIII, or IX and compounds listed inTables 1 and 3 of this invention.

A compound of the invention or a pharmaceutically acceptable salt orsolvate thereof that contains the aforementioned deuterium atom(s) iswithin the scope of the invention. Further, substitution with heavierdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements.

In one aspect, the invention provides a deuterium labeled compoundselected from Table

TABLE 2 Compound # Chemical Structure 10A

In one aspect, a deuterium labeled compound of the invention is apharmaceutically acceptable salt. In one aspect, a deuterium labeledcompound of the invention is a solvate. In one aspect, a deuteriumlabeled compound of the invention is a hydrate.

The present invention relates to pharmaceutical compositions comprisingone of the deuterium labeled compounds of the invention as an activeingredient. In one aspect, the invention provides a pharmaceuticalcomposition comprising at least one deuterium labeled compound offormula I, II, III, IV, V, VI, VII, VIII, or IX or a pharmaceuticallyacceptable salt or solvate thereof and one or more pharmaceuticallyacceptable carrier or excipient. In one aspect, the invention provides apharmaceutical composition comprising at least one compound of Table 2.

The present invention relates to a method of synthesizing a deuteriumlabeled compound of the invention or a pharmaceutically acceptable saltor solvate thereof.

The deuterium labeled compounds of the invention can be prepared usingany of a variety of art-recognized techniques. The deuterium labeledcompounds can generally be prepared by carrying out the proceduresdisclosed in Schemes and the description provided herein. For example, adeuterium labeled compound can be prepared by starting with deuteriumlabeled Compound A or E and/or substituting a readily availabledeuterium labeled reagent for a non-deuterium labeled reagent.

The scheme and description below depicts a general route for theincorporation of deuterium label to produce a deuterium labeled compoundof the invention.

Scheme 3A outlines a preparation for a deuterium labeled compound of theinvention having the structure I. The preparation begins with Compound C(from Scheme 1A described herein). In Step 1, the nitro group ofCompound C is reduced and then the deuterium label is introduced viaformation of a carbamate. For example, the nitro group of Compound C canbe reduced using zinc powder and ammonium chloride in methanol and thecarbamate can be formed using ethyl-d5 chloroformate to provide CompoundI.

The present invention also relates to 18F compounds useful for positronemission tomography (PET) imaging of the distribution of a compound ofthe invention by the imaging of the distribution of the 18F isotopicanalog of the compound, or the functional status of KCNQ2/3voltage-gated potassium channels in a subject. Imaging the KCNQ2/3voltage-gated potassium channels provides information to diagnosediseases associated with deficiencies in the function of the channelssuch as epilepsy, monitor therapy by compounds of the invention, ofother compounds that result in KCNQ2/3 opening.

The invention provides an 18F compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein A is N or C—X₃;X₁, X₂, X₃, X₄, X₅, X₆, X₇, and X₈ are each independently selected fromhydrogen, 19F and 18F; n is 2 or 3, provided that one of X₁, X₂, X₃, X₄,X₅, X₆, X₇, and X₈ is 18F.

While all of the 18F compounds of this invention are useful, certainclasses are preferred. The following paragraphs describe certainpreferred classes of a compound of formula V, wherein:

-   a-4) at least one of X₁, X₂, X₃, X₄, X₅, X₆, X₇, and X₈ is 19F;-   b-4) one of X₁, X₂, X₃, X₄, X₅, X₆, X₇, and X₈ is 19F;-   c-4) two of X₁, X₂, X₃, X₄, X₅, X₆, X₇, and X₈ are 19F;-   d-4) A is N;-   e-4) A is C—X₃ and X₃ is hydrogen;-   f-4) A is C—X₃ and X₃ is 19F;-   g-4) X₆ is 18F;-   h-4) X₁ is 18F;-   i-4) X₆ is 19F; and-   j-4) the remaining X₁, X₂, X₃, X₄, X₅, X₇, and/or X₈ are each    hydrogen.

In one aspect, the invention provides an 18F compound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein X₄, X₅, X₆, X₇and X₈ are each independently selected from hydrogen, 19F, and 18F,provided that one of X₄, X₅, X₆, X₇ and X₈ is 18F.

The following paragraphs describe certain preferred classes of acompound of formula VI, wherein:

-   a-5) at least one of X₄, X₅, X₆, X₇ and X₈ is 19F;-   b-5) one of X₄, X₅, X₆, X₇ and X₈ is 19F;-   c-5) one of X₄, X₅, X₆, X₇ and X₈ is 18F;-   d-5) X₄ is 18F;-   e-5) X₅ is 18F;-   f-5) X₆ is 18F;-   g-5) X₇ is 18F;-   h-5) X₈ is 18F;-   i-5) X₆ is 18F or 19F;-   j-5) X₆ is 19F; and-   k-5) the remaining X₄, X₅, X₆, X₇, and/or X₈ are each hydrogen.

In one aspect, the invention provides an 18F compound of formula VII:

or a pharmaceutically acceptable salt thereof, wherein X₁, X₂, X₃, andX₆ are each independently selected from hydrogen, 18F, and 19F, providedthat one of X₁, X₂, X₃, and X₆ is 18F.

The following paragraphs describe certain preferred classes of acompound of formula VII, wherein:

-   a-6) at least one of X₁, X₂, X₃, and X₆ is 19F;-   b-6) one of X₁, X₂, X₃, and X₆ is 19F;-   c-6) two of X₁, X₂, X₃, and X₆ are 19F;-   d-6) X₆ is 18F and X₁, X₂, and X₃ are each independently selected    from hydrogen and 19F, provided that least one of X₁, X₂, X₃ is 19F;-   e-6) X₆ is 18F and X₁ is 19F;-   f-6) X₆ is 18F and X₂ is 19F;-   g-6) X₆ is 18F and X₃ is 19F;-   h-6) X₆ is H and one of X₁, X₂, and X₃ is 18F;-   i-6) X₆ is H and X₁ is 18F;-   j-6) X₆ is H and X₂ is 18F;-   k-6) X₆ is H and X₃ is 18F;-   l-6) X₁ is 18F or 19F;-   m-6) X₂ is 18F or 19F;-   n-6) X₃ is 18F or 19F;-   o-6) X₆ is 18F or 19F;-   p-6) X₆ is 19F and X₁ is 18F;-   q-6) X₆ is 19F and X₂ is 18F;-   r-6) X₆ is 19F and X₃ is 18F;-   s-6) at least one of X₁, X₂, and X₃ is 19F; and-   t-6) the remaining X₁, X₂, X₃, and/or X₆ are each hydrogen.

In one aspect, the invention provides an 18F compound of formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3, A isN or C—X₃, and X₃ is selected from hydrogen or 19F.

The following paragraphs describe certain preferred classes of acompound of formula VIII, wherein:

-   a-7) A is N;-   b-7) A is C—X₃ and X₃ is hydrogen;-   c-7) A is C—X₃ and X₃ is 19F;-   d-7) n is 2; and-   e-7) n is 3.

In one aspect, the invention provides an 18F compound of formula (IX):

or a pharmaceutically acceptable salt thereof, wherein X₁, X₂, X₄, X₅,X₆, X₇, and X₈ are each independently selected from hydrogen 19F and18F; n is 2 or 3, provided that one of X₁, X₂, X₄, X₅, X₆, X₇, and X₈ is18F.

The following paragraphs describe certain preferred classes of acompound of formula IX, wherein:

-   a-8) at least one of X₁, X₂, X₄, X₅, X₆, X₇, and X₈ is 19F;-   b-8) one of X₁, X₂, X₄, X₅, X₆, X₇, and X₈ is 19F;-   c-8) two of X₁, X₂, X₄, X₅, X₆, X₇, and X₈ are 19F;-   d-8) X₁ is 18F or 19F;-   e-8) X₂ is 18F or 19F;-   f-8) X₆ is 18F or 19F;-   g-8) X₆ is 18F and X₁ is 19F;-   h-8) X₆ is 19F and X₁ is 18F;-   i-8) X₆ is 18F and X₂ is 19F;-   j-8) X₆ is 19F and X₂ is 18F; and-   k-8) the remaining X₁, X₂, X₄, X₅, X₆, X₇, and X₈ are each hydrogen.

It will be understood that the above classes may be combined to formadditional classes, as for example the combination of selections for twoor more substituents. For example,

For formula V, class j-4) can be combined with one of classes a-4),b-4), c-4), g-4), h-4, or i-4);

For formula V, class j-4) can be combined with one of classes a-4),b-4), c-4), g-4), h-4, or i-4), which can be further combined with classd-4), e-4), or f-4);

For formula VI, class k-5) can be combined with one of classes a-5),b-5), c-5), d-5), e-5), f-5), g-5), h-5), i-5), and j-5);

For formula VII, class t-6) can be combined with one of classes a-6),b-6), c-6), e-6), f-6), g-6), h-6), i-6), j-6), k-6), l-6), n-6), o-6),p-6), q-6), r-6), and s-6);

For formula VIII, one of classes a-7), b-7), or c-7) can be combinedwith one of classes d-7) or e-7);

For formula IX, class k-8) can be combined with one of classes a-8),b-8), c-8), d-8), e-8), f-8), g-8), h-8), i-8), and j-8).

In one aspect the invention provide an 18F compound selected from Table3.

TABLE 3 Compound # Chemical Structure 5A

6A

7A

8A

9A

In one aspect, an 18F compound of the invention is a pharmaceuticallyacceptable salt.

The present invention relates to pharmaceutical compositions comprisingone of the 18F compounds of the invention suitable for parenteralinjection. In one aspect, the invention provides a pharmaceuticalcomposition comprising at least one 18F compound of formulae V, VI, VII,VIII or IX or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carrier or excipient. In one aspect, theinvention provides a pharmaceutical composition comprising at least one18F compound of Table 2.

Methods of Synthesizing 18F Compounds

18F compounds of the invention may be synthesized by reacting aprecursor compound with F-18 fluoride via an S_(n)2 displacement of anappropriate leaving group on the precursor compound. Examples of suchleaving groups include sulfonic acid esters such as toluenesulfonate(tosylate), methanesulfonate (mesylate), or trifluoromethanesulfonate(triflate). The leaving group may also be a halide, a nitro group, atrimethylammonium group, a phosphine oxide (via Mitsunobu reaction), oran internal leaving group (such as an epoxide or cyclic sulfate). Insome embodiments, 18F compounds of the invention can be synthesized fromhighly activated, dry, K18F, which is made more reactive by the additionof potassium sequestering cryptands such as 18-crown-6 or kryptofix[2.2.2].

For some compounds containing aromatic or heterocyclic ring structuresthat are not amenable to nucleophilic substitution by activatedfluoride, an electrophilic fluorination method may be used. Thesemethods include reaction with F-18 fluorine gas (F2) or F-18N-chloromethyl-N-fluorotriethylenediammonium bis(tetrafluoroborate)(F-18-TEDA). Other methods of electrophilic fluorination include the useof the palladium(IV) complex described in Science, 2011, 334, pp.639-642; or the diaryliodonium salts described in Organic & BiomolecularChemistry, 2011, 9, pp. 8346-8355.

The foregoing chemical transformations may be conducted using techniqueswhich would be readily apparent to one of ordinary skill in the art, incombination with the teachings described herein. In some cases, methodsof synthesizing the F-18 compounds of the invention may include the useof one or more reaction solvents. Representative reaction solventsinclude, for example, acetonitrile, acetone, DMF, DMSO, THF,ethylacetate, toluene, dichloromethane and chloroform. The acidity orbasicity of the reaction solution may be controlled by the use of one ormore organic acids or bases, for example, triethylamine ordiisopropylethylamine, or trifluoroacetic acid. In some cases thechemical transformations may be carried out at ambient temperatures orunder elevated temperatures and may be protected from oxygen and waterby nitrogen, argon or helium atmosphere.

In some embodiments, temporary protecting groups may be used to preventother reactive functionality, such as amines, thiols, alcohols, phenols,and carboxylic acids, from participating or interfering in thefluorination reaction. Representative amine protecting groups include,for example, tert-butoxycarbonyl and trityl (removed under acidconditions), Fmoc (removed by the use of secondary amines such aspiperidine), and benzyloxycarbonyl (removed by strong acid or bycatalytic hydrogenolysis). The trityl group may also be used for theprotection of thiols, phenols, and alcohols. In certain embodiments thecarboxylic acid protecting groups include, for example, tert-butyl ester(removed by mild acid), benzyl ester (usually removed by catalytichydrogenolysis), and alkyl esters such as methyl or ethyl (usuallyremoved by mild base). All protecting groups may be removed at theconclusion of the synthesis using the conditions described above for theindividual protecting groups, and the final product may be purified bytechniques which would be readily apparent to one of ordinary skill inthe art, in combination with the teachings described herein.

The present invention relates to a method of synthesizing an 18Fcompound of the invention or a pharmaceutically acceptable salt thereof.There are several methods for synthesizing F-18 compounds of the presentinvention that are comprised of F-18 substituents on aromatic rings:nucleophilic displacement of a leaving group such as bromo, nitro, ortrimethylamino by strongly nucleophilic F-18 fluoride ion (Scheme 3A);palladium-assisted electrophilic aromatic substitution (Schemes 4A, 4B,and 4C); and nickel-assisted aromatic fluorination Scheme 5A). In eachof these reaction schemes the aromatic ring that is to be substituted byF-18 is shown bearing a substituent -R, wherein R represents theremainder of the desired molecule of the present invention.

The process described above in Scheme 3A involves acquiring 18F-fluorideas an aqueous solution, available from a number of commercialradiopharmacies, potassium carbonate and Kryptofix[2.2.2] added and thewater evaporated to yield a dry residue. A solution of the Compound 1dissolved in acetonitrile is added and the mixture is heated undernitrogen at elevated temperature for the time necessary to complete thereaction. Alternatives solvents to acetonitrile such asdimethylsulfoxide can be used to allow higher heating temperatures, e.g.up to 130 C.

Schemes 4A, 4B, and 4C: Palladium-Assisted Electrophilic AromaticSubstitution

The process involves making a palladium(II)-aryl complex with the arylgroup attached to the palladium atom at the point of substitution with18F desired using standard organometallic chemistry reaction conditions.Particularly effective is to make a alkylboronate-substituted aryl groupand to react that with the palladium(II) acetate complex shown in Scheme4A in an organic solvent.

A 18F-Palladium(IV)-Fluoride Complex is then Made as Shown in Scheme 4B.

18F-Fluoride as an aqueous solution, available from a number ofcommercial radiopharmacies, potassium bicarbonate and 18-crown-6 arecombined and the water evaporated to yield a dry residue. A solution ofthe compound 4 dissolved in acetone is added to form compound 5, the18F-palladium(IV)-fluoride complex.

The 18F-palladium(IV)-fluoride complex is then reacted withpalladium(II)-aryl complex made in Scheme 4A in acetone at elevatedtemperature for the period of time necessary to complete the reaction.This reaction is shown in Scheme 4C.

Schemes 5A, 5B, and 5C: Nickel-Assisted Aromatic Fluorination

This process involve synthesizing a nickel(II) aryl complex with thearyl group attached to the nickel atom at the point of substitution with18F desired using standard organometallic chemistry reaction conditions.Particularly effective is to react an arylbromide with thenickel(0)cyclooctadiene) complex, Ni(COD)₂ followed by reacting with the2-(2-pyridinyl)anilinosulfonamide silver salt shown in Scheme 5A.

The nickel(II)-aryl complex is then combined simultaneously with acommercially available hypervalent iodine oxidant and 18F-fluoride as adilute aqueous solution in acetonitrile containing 18-crown-6. Thisprocess step is shown in Scheme 5B. The desires 18F-aryl compound ismade nearly instantaneously at room temperature.

Methods of Use

The present invention relates to methods for the use of compounds of theinvention. The compounds of the invention have a useful pharmacologicalactivity spectrum and are therefore particularly suitable for theprophylaxis and/or treatment of diseases or disorders.

The present invention provides the use of a compound of the inventionfor the preparation of a medicament for administration to a subject foruse in the treatment or prevention of disorders.

In one aspect, the invention provides the use of a compound of theinvention in the preparation of a medicament for administration to asubject for use in the treatment or prevention of conditions amelioratedby KCNQ2/3 potassium channel opening. In one aspect, the inventionprovides a method treating a subject suffering from or susceptible toconditions ameliorated by KCNQ2/3 potassium channel opening, comprisingadministering to the subject in need thereof an effective amount of acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof.

In one aspect, the invention provides a method of treating or preventingepilepsy in a subject in need thereof comprising administering to thesubject an effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate thereof.

In one aspect, the invention provides a method of producing ananti-epileptic, muscle relaxing, fever reducing, peripherally analagesicor anti-convulsive effect in a subject in need thereof comprisingadministering to the subject an effective amount of a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the invention provides compounds that are useful as ananti-convulsant. They are therefore useful in treating epilepsy. In oneaspect, the invention provides a method of treating a subject sufferingfrom or susceptible to epilepsy comprising administering to the subjectin need thereof an effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate thereof. Compound of theinvention may be used to improve the condition of a host, typically ahuman being, suffering from epilepsy. They may be employed to alleviatethe symptoms of epilepsy in a host. “Epilepsy” is intended to includethe following seizures:—simple partial seizures, complex partialseizures, secondary generalized seizures, generalized seizures includingabsence seizures, myoclonic seizures, clonic seizures, tonic seizures,tonic clonic seizures and atonic seizures.

Partial-onset seizures are the most common type of seizure in adultpatients. For partial seizures, there is a focal epileptic zone (site ofseizure onset), and seizure activity is initially limited to onehemisphere. Partial seizures can be further sub-divided into simplepartial (without impairment of consciousness), complex partial (withimpairment of consciousness with or following a simple partial onset)and secondarily generalized (i.e., partial seizures, either simple orcomplex, which evolve to generalized tonic-clonic seizures). Simplepartial seizures, depending on the anatomical site of origin of theseizure, may have motor, somatosensory or special sensory, autonomic orpsychic signs or symptoms. In one aspect, the invention provides amethod for the adjunctive treatment of adults with partial-onsetseizures comprising administering to the subject an effective amount ofa compound of the invention or a pharmaceutically acceptable saltthereof.

In one aspect, the invention provides a method for the treating asubject suffering from or susceptible to epilepsy comprisingadministering to the subject in need thereof an effective amount of acombination of a compound of the invention and one or moreanti-epileptic drugs (AEDs). There are different types of AEDs. Forexample, narrow-spectrum AEDs include e.g., phenyloin (Dilantin),phenobarbital, carbamazepine (Tegretol), oxcarbazepine (Trileptal),gabapentin (Neurontin), pregabalin (Lyrica), lacosamide (Vimpat), andvigabatrin (Sabril). Broad spectrum AEDs include e.g., valproic acid(Depakote), lamotrigine (Lamictal), topiramate (Topamax), zonisamide(Zonegran), levetiracetam (Keppra), clonazepam (Klonopin), andrufinamide (Banzel). In one aspect, the AED is any AED. In one aspect,the AED is a narrow spectrum AED. In one aspect, the AED is a broadspectrum AED.

In one aspect, the invention provides a method of treating or preventinga neurotransmission disorder, CNS disorder, functional bowel disorder,neurodegenerative disease, or tinnitus in a subject in need thereofcomprising administering to the subject an effective amount of acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof.

In one aspect, the invention provides a method of treating or preventinga cognitive disorder or migraine in a subject in need thereof comprisingadministering to the subject an effective amount of a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the invention provides a method of treating or preventingmigraine, bipolar disorder, unipolar depression, functional boweldisorders, or tinnitus in a subject in need thereof comprisingadministering to the subject an effective amount of a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the invention provides compounds that are useful in thetreatment of CNS disorders such as bipolar disorder, alternatively knownas manic depression. Type I or II bipolar disorder may be treated. Thecompounds may thus be used to improve the condition of a human patientsuffering from bipolar disorder. They may be used to alleviate thesymptoms of bipolar disorder in a host. The compounds may also be usedin the treatment of unipolar depression, ataxia, myokimia and anxiety.

In one aspect, the invention provides compounds that are useful in thetreatment of functional bowel disorders which include non-ulcerdyspepsia, non-cardiac chest pain and in particular irritable bowelsyndrome. Irritable bowel syndrome is a gastrointestinal disordercharacterized by the presence of abdominal pain and altered bowel habitswithout any evidence of organic disease. The compounds may thus be usedto alleviate pain associated with irritable bowel syndrome. Thecondition of a human patient suffering from irritable bowel syndrome maythus be improved.

In one aspect, the invention provides compounds that are useful asanalgesics. They are therefore useful in treating or preventing pain.They may be used to improve the condition of a host, typically a humanbeing, suffering from pain. They may be employed to alleviate pain in ahost. Thus, the compounds may be used as a pre-emptive analgesic totreat acute pain such as musculoskeletal pain, post-operative pain andsurgical pain, chronic pain such as chronic inflammatory pain (e.g.rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. postherpetic neuralgia, trigeminal neuralgia and sympathetically maintainedpain) and pain associated with cancer and fibromyalgia. The compoundsmay also be used in the treatment or prevention of pain associated withmigraine. The compounds may also be used in the treatment of the pain(both chronic and acute), fever and inflammation of conditions such asrheumatic fever; symptoms associated with influenza or other viralinfections, such as the common cold; lower back and neck pain; headache;toothache; sprains and strains; myositis; neuralgia; synovitis;arthritis, including rheumatoid arthritis; degenerative joint diseases,including osteoarthritis; gout and ankylosing spondylitis; tendinitis;bursitis; skin related conditions, such as psoriasis, eczema, burns anddermatitis; injuries, such as sports injuries and those arising fromsurgical and dental procedures.

In one aspect, the invention provides a method of producing an analgesiceffect in a subject in need thereof comprising administering to thesubject an effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate thereof. In one aspect, theanalgesic effect is a neuroprotective effect. In one aspect, theanalgesic effect is a centrally acting analgesic effect.

In one aspect, the invention provides compounds that are useful in thetreatment of neurodegenerative diseases, such as Alzheimer's disease,ALS, motor neuron disease, Parkinson's disease, macular degeneration andglaucoma. The compounds of the invention may also be useful inneuroprotection and in the treatment of neurodegeneration followingstroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinalcord injury or the like. In one aspect, compounds of the invention arefurther useful in the treatment of tinnitus.

In one aspect, the invention provides compounds that are useful in thetreatment of migraine.

In one aspect, the invention provides a method of preventing or reducingdependence on, or preventing or reducing tolerance, or reversetolerance, to a dependence-inducing agent in a subject in need thereofcomprising administering to the subject an effective amount of acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof. Examples of dependence inducing agents include opioids(e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g.cocaine) and nicotine.

In one aspect, the invention provides a method of treating or preventingcancer, inflammatory disease, or ophthalmic disease in a subject in needthereof comprising administering to the subject an effective amount of acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof.

In one aspect, the invention provides compounds that inhibit cellularand neoplastic transformation and metastatic tumor growth and hence areuseful in the treatment of certain cancerous diseases, such as coloniccancer.

In one aspect, the invention provides compounds that inhibitinflammatory processes and therefore are of use in the treatment ofasthma, allergic rhinitis and respiratory distress syndrome;gastrointestinal conditions such as inflammatory bowel disease, Chron'sdisease, gastritis, irritable bowel syndrome and ulcerative colitis; andthe inflammation in such diseases as vascular disease, migraine,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis,sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis,gingivitis, conjunctivitis and myocardial ischemia.

In one aspect, the invention provides compounds that are useful in thetreatment of ophthalmic diseases such as retinitis, retinopathies,uveitis and of acute injury to the eye tissue.

In one aspect, the invention provides compounds that are useful for thetreatment of cognitive disorders such as dementia, particularlydegenerative dementia (including senile dementia, Alzheimer's disease,Pick's disease, Huntington's chorea, Parkinson's disease andCreutzfeldt-Jakob disease), and vascular dementia (includingmulti-infarct dementia), as well as dementia associated withintracranial space occupying lesions, trauma, infections and relatedconditions (including HIV infection), metabolism, toxins, anoxia andvitamin deficiency; and mild cognitive impairment associated withageing, particularly Age Associated Memory Loss; and learningdeficiencies.

In one aspect, the invention provides a method of producing ananxiolytic effect in a subject in need thereof comprising administeringto the subject an effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate thereof. In one aspect, theinvention provides a method for the treatment of anxiety and its relatedpsychological and physical symptoms. Anxiolytics have been shown to beuseful in the treatment of anxiety disorders.

In one aspect, the invention provides compounds for treatment. In oneaspect, the invention provides compounds for prophylaxis. In one aspect,the invention provides compound for alleviation of established symptoms.

In one aspect, the invention provides pharmaceutical formulations thatcontain between about 10 to about 100, about 30 to about 60 mg of theactive component(s) of the invention.

Administration may for example be in the form of tablets, capsules,pills, coated tablets, suppositories, ointments, gels, creams, powders,dusting powders, aerosols or in liquid form. Liquid application formsthat may for example be considered are: oils or alcoholic or aqueoussolutions as well as suspensions and emulsions. In one aspect, theinvention provides forms of application that are tablets that containbetween 30 and 60 mg or solutions that contain between 0.1 to 5 percentby weight of active substance.

In one aspect, a single dose of the active components of the inventioncan for example lie a) in the case of oral medicinal forms between about20 and about 80 mg, about 30 to about 60 mg; b) in the case ofparenteral medicinal forms (for example intravenous, intramuscular)between about 5 to about 20 mg, about 8 to about 16 mg. (The doses arein each case related to the free base)

In one aspect, it is for example possible to recommend 3 times daily 1to 3 tablets containing about 30 to about 60 mg of active substance orfor example in the case of intravenous injection 1 to 3 times daily oneampoule of about 3 to about 5 ml content with about 8 to about 16 mgsubstance. In the case of oral administration, the minimum daily dose isfor example about 90 mg; the maximum daily dose in oral administrationshould not exceed about 270 mg.

For the treatment of dogs and cats, the oral individual dose isgenerally between about 2 and about 20 mg/kg body weight; the parenteraldose about between about 1 and about 5 mg/kg body weight.

In one aspect, a compound of the invention is used in human medicine. Inone aspect, the compound of the invention is used in veterinarymedicine. In one aspect, a compound of the invention is used inagriculture. In one aspect, a compound of the invention is used alone ormixed with other pharmacologically active substances.

In one aspect, the invention provides a medical device containing acompound of the invention or a pharmaceutically acceptable salt orsolvate thereof.

Methods of Imaging

The 18F compounds of the invention may be used in methods of imaging asubject to diagnose the presence, extent or response to therapy of adisease process. For example, the method of imaging may compriseadministering the 18F compound of the invention to the subject byintravenous injection as a bolus or an infusion, or any other methodknown to be appropriate for imaging a subject, and imaging the area ofthe subject wherein the process of imaging interest is located.

The useful dosage to be administered and the particular mode ofadministration will vary depending on factors such as age, weight, andparticular region of the body to be imaged, as well as the diagnosticuse contemplated. Typically, dosage is administered at lower levels andincreased until a desirable diagnostic effect (e.g. production of animage) is achieved. In some embodiments, the 18F compounds may beadministered by intravenous injection, usually in saline solution, at adose of about 0.1 to about 100 mCi per 70 kg body weight (and allcombinations and subcombinations of dosage ranges and specific dosagestherein), or, in some embodiments, at a dose of about 0.5 mCi to about50 mCi per subject. Imaging is performed using techniques well known tothose of ordinary skill in the art.

The 18F compounds of the invention may be formulated for parenteraladministration. These formulations must be sterile and non-pyrogenic andoptionally may be comprised of one or more pharmaceutically compatiblesolvent, buffer, neutralization aid, stabilization aid, andsolubilization aid.

Some non-limiting examples of buffers useful combination with the 18Fcompounds include phosphate, citrate, sulfosalicylate, and acetate. Amore complete list can be found in the United States Pharmacopoeia.

Some non-limiting examples of stabilization aids include ethanol,ascorbic acid, cysteine, monothioglycerol, sodium bisufite, sodiummetabisulfite, gentisic acid, and inositol.

Some non-limiting examples of solubilization aids include ethanol,glycerin, polyethyleneglycol, propylene glycol, polyoxyethylene sorbitanmonooleate, sorbitan monooleate, polysorbates,poly(oxyethylene)-poly(oxypropylene)-poly(oxy ethylene) blockco-polymers, and lecithin.

In one aspect, the invention provides 18F compounds for PET imaging.

In one aspect, the invention provides a method of imaging thebiodistribution of an 18F compound of the invention comprisingadministering to a subject an effective amount of a the compound or apharmaceutically acceptable salt thereof and imaging the subject usingpositron emission tomography.

In one aspect, the invention provides a method of imaging the functionalstatus of the KCNQ2/3 potassium channel in a subject comprisingadministering to a subject in need thereof an effective amount of an 18Fcompound of the invention or a pharmaceutically acceptable salt thereofand imaging the subject using positron emission tomography.

In one aspect, the invention provides a method of imaging aneurotransmission disorder, CNS disorder, cognitive disorder, orneurodegenerative disease in a subject in need thereof comprisingadministering to the subject an effective amount of an 18F compound ofthe invention or a pharmaceutically acceptable salt thereof and imagingthe subject using positron emission tomography.

In one aspect, an 18F compound of the invention is administered to ahuman subject.

The following Examples are illustrative and should not be interpreted inany way so as to limit the scope of the invention.

EXAMPLES Example 1 Experimental Procedures and Compound CharacterizationExample 1A Synthesis of ethyl(2-amino-3-fluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate (Compound 1Ain Table 1)

2,3-Difluoro-6-nitroaniline (2)

A solution of 1,2,3-trifluoro-4-nitrobenzene (1) (1.00 g, 5.64 mmol,1.00 equiv) in methanolic ammonia (1.5 mL) was taken in microwave vialand heated to 70° C. for 90 min in the microwave. The solvent wasevaporated under vacuum to give crude; which was purified by silica gelcolumn chromatography (EtOAc/Hexane 1:49) to furnish compound 2 (0.350g, 35.6%) as yellow solid. TLC: 10% EtOAc/Hexane (R_(f): 0.10); ¹H NMR(500 MHz, DMSO-d₆): δ 7.94-7.91 (m, 1H), 7.51 (s, 2H), 6.75-6.70 (m,1H); LC-MS: m/z=173 (M⁺-1) at RT 3.15 (99.8% purity)

2-Fluoro-N1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (3)

To a stirred suspension of compound 2 (0.100 g, 0.570 mmol, 1.00 equiv)in dry DMSO (4.6 mL) were added 4-fluorobenzylamine (0.210 g, 1.72 mmol,3.00 equiv) followed by Et₃N (69.6 mg, 0.690 mmol, 1.20 equiv) and I₂(catalytic, 1.00 mg). The reaction mixture was heated to 120° C. andstirred at 120° C. for 24 h. After consumption of the starting material(by TLC), the reaction mixture was cooled to RT, diluted with water (25mL) and extracted with EtOAc (2×25 mL). The separated organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give crude; which was purified by silica gel columnchromatography (EtOAc/Hexane 2:23) to afford compound 3 (0.100 g, 62.5%)as yellow solid. TLC: 20% EtOAc/Hexane (R_(f): 0.20); ¹H NMR (400 MHz,CDCl₃): δ 7.87 (dd, J=1.60, 9.60 Hz, 1H), 7.31-7.28 (m, 2H), 7.08-7.03(m, 2H), 6.11-6.03 (m, 3H, 2Exc), 4.82 (br s, 1H, Exc), 4.44 (d, J=5.2Hz, 2H); LC-MS: m/z=278 (M⁺-1) at RT 3.64 (91.7% purity)

Ethyl (2-amino-3-fluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate (1A)

To a stirred solution of compound 3 (0.800 g, 2.86 mmol, 1.00 equiv) inmethanol (7.2 mL) was added zinc powder (0.930 g, 14.3 mmol, 5.00 equiv)followed by ammonium chloride solution (0.760 g, 14.3 mmol, 5.00 equiv)dropwise. After being stirred at RT for 5 h, DIPEA (0.460 g, 3.58 mmol,1.25 equiv) and ethyl chloroformate (0.310 g, 2.87 mmol, 1.00 equiv)were added to reaction mixture at 10° C. and the stirring was continuedfor another 3 h at RT. After consumption of the starting material (byTLC), the reaction mixture was diluted with water (24 mL) and stirredfor 1 h to give the solid. The obtained solid was filtered, dissolved inEtOAc (15 mL) and again filtered the un-dissolved solid. The filtratewas evaporated and recrystallized using n-hexane to afford compound 1A(0.250 g, 27.0%) as brown solid. TLC: 50% EtOAc/Hexane (R_(f): 0.20) ¹HNMR (500 MHz, CDCl₃): δ 7.31 (t, J=7.5 Hz, 2H), 7.02 (t, J=6.8 Hz, 2H),6.75 (d, J=6.8 Hz, 1H), 6.07 (t, J=6.8 Hz, 1H), 4.31 (s, 2H), 4.22-4.18(m, 3H), 3.84 (br s, 2H, Exc), 1.29 (t, J=5.6 Hz, 3H); UPLC purity:91.0%; LC-MS: m/z=322 (M⁺-1) at RT 3.37 (82.8%)

Example 1B Synthesis of ethyl(2-amino-6-fluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate (Compound 2Ain Table 1)

N,N-Bis-ethoxycarbonyl-(4-bromo-2-fluoro-6-nitroaniline) (2)

To a stirred solution of 4-bromo-2-fluoro-6-nitroaniline (1) (0.500 g,2.12 mmol, 1.00 equiv) in THF (20 mL) was added NaH (0.250 g, 6.40 mmol,3.00 equiv) portion wise at 0° C. After being stirred for 1 h at RT,ethyl chloroformate (1.00 mL, 10.6 mmol, 5.00 equiv) was added drop wiseto the reaction mixture at 0° C. The reaction mixture was heated underreflux temperature for 36 h. After consumption of the starting material(by TLC), the reaction was quenched with saturated NH₄Cl solution andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give crude; which was purified by silica gel columnchromatography (EtOAc/Hexane 1:4) to furnish compound 2 (0.350 g, 43.0%)as yellow solid.

TLC: 30% EtOAc/Hexane (R_(f): 0.40); ¹H NMR (500 MHz, CDCl₃): δ 8.08 (s,1H), 7.65 (d, J=6.5 Hz, 1H), 4.27 (q, J=7.0 Hz, 4H), 1.25 (t, J=7.0 Hz,6H).

Ethyl (2-fluoro-4-((4-fluorobenzyl)amino)-6-nitrophenyl)carbamate (3)

To a stirred solution of compound 2 (0.300 g, 0.790 mmol, 1.00 equiv) in1,4-dioxane (10 mL) were added 4-fluorobenzylamine (0.200 g, 1.58 mmol,2.00 equiv), Cs₂CO₃ (0.500 g, 1.50 mmol, 2.00 equiv) followed by Pd₂(dba)₃ (0.072 g, 0.079 mmol, 10 mol %) and Xantphos (0.045 g, 0.079mmol, 10 mol %) at RT. The reaction mixture was heated at 90° C. andstirred at the same temperature for 8 h. After consumption of thestarting material (by TLC), the reaction mixture was concentrated undervacuum. The obtained residue was diluted with water (50 mL) andextracted with EtOAc (2×50 mL). The combined organic extracts were driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum. The crudematerial was purified by silica gel column chromatography (EtOAc/Hexane2:23) to afford compound 3 (0.140 g, 50.3%) as yellow solid. TLC: 40%EtOAc/Hexane (R_(f): 0.25); ¹H NMR (500 MHz, CDCl₃): δ 7.31-7.28 (m,2H), 7.06 (t, J=8.5 Hz, 1H), 7.00 (s, 2H), 6.91 (br s, 1H), 6.60 (d,J=9.5 Hz, 1H), 4.46 (br s, 1H), 4.31 (d, J=4.4 Hz, 2H), 4.20 (q, J=7.0Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); LC-MS: m/z=350 (M⁺-1) at RT 3.69 (97.8%purity).

Ethyl (2-amino-6-fluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate (2A)

To a stirred solution of compound 3 (0.075 g, 0.24 mmol, 1.0 equiv) inmethanol (3 mL) was added zinc powder (0.0800 g, 1.22 mmol, 5.00 equiv)followed by ammonium chloride solution (0.065 g, 1.2 mmol, 5.0 equiv) inwater (1 mL). The reaction mixture was stirred at RT for 4 h. Afterconsumption of the starting material (by TLC), the reaction mixture wasdiluted with DCM (10 mL), water (10 mL) and filtered through a pad ofcelite. The organic layer was separated from filtrate and the aqueouslayer was extracted with DCM (2×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄, concentrated under vacuum to givecrude; which was purified by silica gel column chromatography(EtOAc/Hexane, 1:4) to afford compound 2A (0.050 g, 71%) as an off-whitesolid. TLC: 40% EtOAc/Hexane (R_(f): 0.20); ¹H NMR (400 MHz, CDCl₃): δ7.32-7.29 (m, 2H), 7.04 (t, J=8.8 Hz, 2H), 5.84 (d, J=9.6 Hz, 1H), 5.78(s, 1H), 4.25-4.18 (m, 4H), 4.04-3.96 (m, 3H), 1.30 (t, J=6.8 Hz, 3H);LC-MS: m/z=322 (M⁺+1) at RT 3.38 (99.0% purity); UPLC purity: 99.5%.

Example 1C Synthesis of ethyl(2-amino-5-fluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate (Compound 3Ain table 1)

4,5-Difluoro-2-nitroaniline (2)

To a solution of 1,2,4-trifluoro-5-nitrobenzene (1) (5.00 g, 28.0 mmol,1.00 equiv) in methanol (5 mL) was added methanolic ammonia (15 mL) andtaken in microwave vial. The reaction mixture was heated in microwave at70° C. for 90 min. The reaction mixture was cooled to RT and removed thesolvent from the reaction under reduced pressure to give crude; whichwas purified by silica gel column chromatography (EtOAc/Hexane 1:4) tofurnish compound 2 (0.600 g, 12.0%) as yellow solid. TLC: 30%EtOAc/Hexane (R_(f): 0.35); ¹H NMR (500 MHz, CDCl₃): δ 8.00 (t, J=9.0Hz, 1H), 6.65-6.58 (m, 1H), 6.08 (br s, 2H).

6-Fluoro-N1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (3)

To a stirred suspension of compound 2 (0.600 g, 3.40 mmol, 1.00 equiv)in dry DMSO (15 mL) was added 4-fluorobenzylamine (1.20 g, 10.0 mmol,3.00 equiv) followed by Et₃N (0.500 mL, 4.10 mmol, 1.20 equiv) and I₂(catalytic, 1.00 mg). The reaction mixture was heated to 120° C. andstirred at 120° C. for 16 h. After consumption of the starting material(by TLC), the reaction mixture was cooled to RT, diluted with water (25mL) and extracted with EtOAc (2×50 mL). The separated organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give crude; which was purified by silica gel columnchromatography (EtOAc/Hexane 2:3) to afford compound 3 (0.550 g, 52.0%)as yellow solid. TLC: 70% EtOAc/Hexane (R_(f): 0.20); ¹H NMR (400 MHz,DMSO-d₆): δ 7.60-7.54 (m, 2H), 7.38-7.32 (m, 4H), 7.17 (t, J=8.8 Hz,2H), 5.92 (d, J=8.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H); LC-MS: m/z=278(M⁺-1) at RT 3.59 (99.4% purity).

Ethyl (2-amino-5-fluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate (3A)

To a stirred solution of compound 3 (0.400 g, 1.40 mmol, 1.00 equiv) inmethanol (10 mL) was added zinc powder (0.470 g, 7.10 mmol, 5.00 equiv)followed by ammonium chloride solution (0.380 g, 9.10 mmol, 5.00 equiv)drop wise. After being stirred for 5 h at RT, DIPEA (0.155 g, 1.54 mmol,1.10 equiv) and ethyl chloroformate (0.151 g, 1.40 mmol, 1.00 equiv)were added to reaction mixture at 0° C. and the stirring was continuedfor another 3 h at RT. After consumption of the starting material (byTLC), the reaction mixture was diluted with water (25 mL) and Extractedwith EtOAc (2×75 mL). The separated organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive crude; which was purified by silica gel column chromatography(EtOAc/Hexane 1:4) to afford to compound 3A (0.100 g, 21.0%) as brownsolid. TLC: 40% EtOAc/Hexane (R_(f): 0.50); ¹HNMR (400 MHz, DMSO-d₆): δ8.27 (br s, 1H), 7.39-7.34 (m, 2H), 7.12 (t, J=8.8 Hz, 2H), 6.81-6.78(m, 1H), 5.93 (d, J=9.2 Hz, 1H), 5.79 (t, J=6.4 Hz, 1H), 4.42 (s, 2H),4.22 (d, J=6.0 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H);LC-MS: m/z=322 (M⁺+1) at RT 3.54 (95.8% purity); UPLC purity: 98.8%

Example 1D Synthesis of ethyl(2-amino-3,5-difluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate(Compound 4A in Table 1)

2,3,4-Trifluoro-6-nitroaniline (2)

A solution of 1,2,3,4-tetrafluoro-5-nitrobenzene (1) (1.50 g, 7.69 mmol,1.00 equiv) and NH₃ in THF (3 mL) was taken in a sealed tube and stirredat RT for 16 h. After 16 h, TLC monitoring indicated the presence ofunreacted starting material and formation of the desired product. Thesolvent from the reaction was removed under reduced pressure to givecrude; which was purified by silica gel column chromatography(EtOAc/Hexane 1:19) to furnish compound 2 (0.200 g, 14.0%) as yellowsolid. TLC: 20% EtOAc/Hexane (R_(f): 0.45); ¹H NMR (400 MHz, CDCl₃): δ7.88-7.83 (m, 1H), 6.10 (br s, 2H, Exc); LC-MS: m/z=191 (M⁺-1) at RT3.14 (99.4% purity)

2,6-Difluoro-N1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (3)

To a stirred suspension of compound 2 (0.060 g, 0.31 mmol, 1.0 equiv) indry DMSO (0.3 mL) was added 4-fluorobenzylamine (0.117 g, 0.940 mmol,3.00 equiv) followed by Et₃N (54.0 μL, 0.370 mmol, 1.20 equiv) and I₂(catalytic, 1.0 mg). The reaction mixture was heated to 120° C. andstirred at 120° C. for 16 h. After consumption of the starting material(by TLC), the reaction mixture was cooled to RT, diluted with water (25mL) and extracted with EtOAc (2×50 mL). The separated organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give crude; which was purified by silica gel columnchromatography (EtOAc/Hexane 2:23) to afford compound 3 (0.064 g, 69%)as yellow solid. TLC: 25% EtOAc/Hexane (R_(f): 0.20); ¹H NMR (400 MHz,CDCl₃): δ 7.67 (dd, J=2.0, 12.8 Hz, 1H), 7.31-7.28 (m, 2H), 7.05 (t,J=6.8 Hz, 2H), 6.05 (br s, 2H, Exc), 4.63 (d, J=6.0 Hz, 2H), 4.53 (br s,1H, Exc); LC-MS: m/z=296 (M⁺-1) at RT 3.64 (98.8% purity)

Ethyl (2-amino-3,5-difluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate(4A)

To a stirred solution of compound 3 (0.062 g, 0.21 mmol, 1.0 equiv) inmethanol (0.560 mL) was added zinc powder (0.068 g, 1.04 mmol, 5.00equiv) followed by ammonium chloride solution (55.3 mg, 1.04 mmol, 5.00equiv) drop wise. After being stirred for 4 h at RT, DIPEA (48.0 μL,0.260 mmol, 1.25 equiv) and ethyl chloroformate (20.0 μL, 0.210 mmol,1.00 equiv) were added to reaction mixture at 10° C. and the stirringwas continued for another 2 h at RT. After consumption of the startingmaterial (by TLC), the reaction mixture was diluted with water (25 mL)and extracted with EtOAc (2×75 mL). The separated organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give crude; which was purified by neutral alumina columnchromatography (EtOAc/Hexane 18:82) to afford to compound 4A (0.017 g,21%) as an off-white solid. TLC: 50% EtOAc/Hexane (R_(f): 0.50); ¹H NMR(500 MHz, CDCl₃): δ 7.30-7.27 (m, 2H), 7.00 (t, J=8.5 Hz, 2H), 6.88 (d,J=11.5 Hz, 1H), 6.26 (br s, 1H, Exc), 4.40 (d, J=6.0 Hz, 2H), 4.21 (q,J=7.0 Hz, 2H), 3.75 (br s, 1H, Exc), 3.50 (s, 2H, Exc), 1.30 (t, J=7.0Hz, 3H); LC-MS: m/z=340 (M⁺+1) at RT 3.46 (94.3% purity); UPLC purity:95.2%

Example 1E Synthesis of ethyl-d5(2-amino-3-fluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate (Compound10A in Table 3)

To a stirred solution of compound 3 (1.00 equiv), prepared as in Example1A, in methanol (7.2 mL) is added zinc powder (5.00 equiv) followed byammonium chloride solution (5.00 equiv) dropwise. After stirring at RTfor 5 h, DIPEA (1.25 equiv) and ethyl-d5 chloroformate (1.00 equiv) areadded to the reaction mixture at 10° C. and the stirring is continuedfor another 3 h at RT. After consumption of the starting material (byTLC), the reaction mixture is diluted with water (24 mL) and stirred for1 h to give the solid. The obtained solid is filtered, dissolved inEtOAc (15 mL) and again filtered to remove the un-dissolved solid. Thefiltrate is evaporated and recrystallized using n-hexane to affordcompound 10A.

Example 2 Experimental Procedures for 18F Compounds Example 2A Synthesisof [¹⁸F]-ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate([¹⁸F]-Ezogabine) (Compound 5A in Table 2)

3-Fluoro-6-nitroaniline

A solution of 1,3-difluoro-4-nitrobenzene (1) (1.59 g, 10.0 mmol, 1.00equiv) in methanolic ammonia (1.5 mL) is taken in microwave vial andheated to 70° C. for 90 min in a microwave. The solvent is evaporatedunder vacuum to give a crude mixture, which is purified by silica gelcolumn chromatography (Ethyl acetate/Hexane) to furnish the desiredproduct.

N1-(4-phenylboronic acid methyl)-4-nitrobenzene-1,3-diamine (3)

A round bottom flask is charged with 3-fluoro-6-nitroaniline (2) (1.00g, 6.40 mmol, 1.00 equiv) and 4-Phenylboronic acid pinacolester (4.47 g,19.2 mmol, 3.00 equiv). Dry DMF (25 mL) is then added followed by Et₃N(0.775 g, 7.68 mmol, 1.20 equiv) and I₂ (catalytic, 1.00 mg). Thereaction mixture is heated to 120° C. and stirred at 120° C. for 24 h.The reaction mixture is then cooled to RT, diluted with water (75 mL)and extracted with Ethyl acetate (2×60 mL). The organic layer is driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give crude material, which is purified by silica gel columnchromatography (Hexane/Hexane) to afford compound 3 as the desiredproduct.

Ethyl (2-amino-4-((4-benzylboronicacidpinacolester)amino)phenyl)carbamate (4)

To a stirred solution of compound 3 (1.00 g, 2.71 mmol, 1.00 equiv) inmethanol (7 mL) is added zinc powder (0.888 g, 13.5 mmol, 5.00 equiv)followed by ammonium chloride solution (0.725 g, 13.55 mmol, 5.00 equiv)dropwise. After 5 h, DIPEA (0.436 g, 3.38 mmol, 1.25 equiv) and ethylchloroformate (0.292 g, 2.71 mmol, 1.00 equiv) are added to reactionmixture at 10° C. and the stirring is continued till consumption ofstarting material (by TLC). The reaction mixture is diluted with water(24 mL) and extracted in ethyl acetate (75 mL), dried using brine andover MgSO4. After concentration the crude material obtained is purifiedto afford the title compound.

Ethyl (2-tertbutoxycarbonylamino-4-((4-benzylboronicacidpinacolester)tertbutoxycarbonyl amino)phenyl)carbamate (5)

To a round bottom flask is charged 4 (1.00 g, 2.45 mmol, 1.00 equiv) andthe compound is dissolved in dichloromethane. Boc anhydride (1.175 g,5.39 mmol, 2.2 equiv) is then added to it and the reaction mixture isstirred at room temperature for 16 hours. The reaction mixture isconcentrated and the residue is purified by silica gel columnchromatography (Hexane/Hexane) to afford compound 5 as the desiredproduct.

Palladium Complex 6

To the palladium complex A (550 mg, 0.996 mmol, 1.00 equiv), synthesizedaccording to Ritter et. al., (Science, 2011, 334, 639-642) in MeOH (5.0mL) and benzene (5.0 mL) at 23° C. is added 5 (527 mg, 1.29 mmol, 1.3equiv) and K₂CO₃ (206 mg, 1.494 mmol, 1.5 equiv). The reaction mixtureis stirred at 23° C. for 10 hours after which it is diluted with CH₂Cl₂(80 mL), filtered through Celite and eluted with additional CH₂Cl₂ (30mL). The solution is then washed with water (3×20 mL) and dried overNa₂SO₄ and concentrated. The residue obtained is then recrystallizedusing CH₂Cl₂/pentane to afford the desired compound 6.

[¹⁸F]-Ezogabine

To the palladium complex B, prepared according to Ritter et. al.,(Science, 2011, 334, 639-642) in 1.5 mL acetone is added 6 and themixture heated to 85 C. for 10 minutes in a securely capped vial. Thevial is cooled and the resulting solution purified via HPLC to obtainthe desired compound 5A (Table 2).

Example 2B

1-fluoro-2,4-dinitro-3-amino benzene (8)

A solution of 1,3-difluoro-2,4-nitrobenzene (7) (2.04 g, 10.0 mmol, 1.00equiv) in methanolic ammonia (3.0 mL) is taken in microwave vial andheated to 70° C. for 90 min in a microwave. The solvent is evaporatedunder vacuum to give a crude mixture, which is purified by silica gelcolumn chromatography (Hexane/Hexane) to furnish the desired product 8.

1,3-dinitro-2-amino-4-(4-fluorobenzyl)amino benzene (9)

A round bottom flask is charged with 8 (2.01 g, 10 mmol, 1 equiv),4-fluorobenzylamine (3.79 g, 30 mmol, 3 equiv) and triethylamine (1.21g, 12 mmol, 1.2 equiv). DMF (40 mL) is then added to the above mixturefollowed by iodine (catalytic, 1 mg). The reaction mixture is thenheated to 120° C. and stirred at 120° C. for 16 hrs after which theflask is allowed to cool to room temperature. The reaction mixture isdiluted with ethyl acetate and washed with water (5×80 mL) and driedwith brine and then over MgSO₄. The suspension is filtered andconcentrated to give a residue, which is purified by silica gel flashchromatography (hexanes/ethyl acetate) to give the desired product (9).

Ethyl (2-amino-3-nitro-4-((4-fluorobenzyl)amino)phenyl)carbamate (10)

To a stirred solution of compound 9 (1.5 g, 5 mmol, 1.00 equiv) inmethanol (7 mL) is added zinc powder (1.64 g, 25 mmol, 5.00 equiv)followed by ammonium chloride solution (1.33 g, 25 mmol, 5.00 equiv)dropwise. After 5 h, DIPEA (0.806 g, 6.25 mmol, 1.25 equiv) and ethylchloroformate (0.54 g, 5 mmol, 1.00 equiv) are added to reaction mixtureat 10° C. and the stirring continued till consumption of startingmaterial (by TLC). The reaction mixture is diluted with water (30 mL)and extracted in ethyl acetate (75 mL), dried using brine and overMgSO₄. After concentration the crude material obtained is purified toafford the title compound.

Ethyl (2-amino-3-[¹⁸F]fluoro-4-((4-fluorobenzyl)amino)phenyl)carbamate([¹⁸F] Fluoro Ezogabine)

¹⁸F deposited on an ORTG/QMA anion exchange column is eluted with asolution of Et₄NHCO₃ in a 4 mL reaction vial. The resulting solution isdried over nitrogen and heat (110° C.). The resulting residue is thendried twice azeotropically using acetonitrile at 95° C. with nitrogenflow. A solution of 10 in 1 mL acetonitrile (anhydrous) is then addedand the vial securely capped and heated to 110° C. for 10 minutes in aheating block. After cooling to room temperature the solution isreconstituted as appropriate and purified to obtain the desired compound6A (Table 2).

Example 2C [¹⁸F] Flupirtine

The preparation of 18F-flupirtine (compound 7A, Table 2) is performedusing the same procedure as described in Example 2A, substituting2,6-difluoro-3-nitropyridine for 1,3-difluoro-4-nitrobenzene.

Example 2D [¹⁸F] Fluoroflupirtine

The preparation of 18F-Fluoroflupirtine (compound 8A, Table 2) isperformed using the same procedure as described in Example 2B,substituting 2,6-difluoro-3,4-dinitropyridine for1,3-difluoro-2,4-nitrobenzene.

Example 2E Synthesis of ethyl(2-amino-3-fluoro-4-((4-[¹⁸F]fluorobenzyl)amino)phenyl)carbamate(Compound 9A in Table 2)

Synthesis of 2,3-difluoro-6-nitroaniline (2)

A solution of 1,2,3-trifluoro-4-nitrobenzene (1) (1.0 g, 5.6 mmol, 1.00equiv.) in freshly prepared methanolic ammonia (3 mL) was charged to amicrowave vial and heated to 70° C. for 90 min in a microwave. Thesolvent was evaporated under reduced pressure to give a crude mixture,which was purified by silica gel column chromatography (Ethylacetate/Hexane) to furnish the desired product (2, 0.85 gm, 81%).

Synthesis of 2-fluoro-3-(4-bromobenzyl)-6-nitroaniline (3)

A round bottom flask was charged with 2,3-difluoro-6-nitroaniline (0.50g, 2.87 mmol, 1.00 equiv.) and 4-bromobenzylamine (0.959 g, 5.15 mmol,1.80 equiv.). Dimethyl sulfoxide (2.5 mL) was then added flowed by Et₃N(0.968 mL, 6.88 mmol, 2.40 equiv.) and I₂ (catalytic, 10 mg). Thereaction mixture was heated to 120° C. and stirred for 3 h. The reactionmixture was then cooled to ambient temperature, diluted with water (75mL) and extracted with Ethyl acetate (2×60 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give crude material, which was purified by silica gel columnchromatography (10% ethyl acetate/hexane) to afford compound 3 as thedesired product (0.869 g, 89%).

Synthesis of Ethyl(2-amino-3-fluoro-4-((4-bromobenzyl)amino)phenyl)carbamate (4)

To a stirred solution of compound 3 (0.90 g, 2.64 mmol, 1.00 equiv.) inmethanol (7.9 mL) was added zinc powder (0.864 g, 13.2 mmol, 5.00equiv.) followed by ammonium chloride solution (0.706 g, 13.2 mmol, 5.00equiv.) drop wise. After 5 h, DIPEA (0.426 g, 3.3 mmol, 1.25 equiv.) andethyl chloroformate (0.286 g, 2.64 mmol, 1.00 equiv.) were added to thereaction mixture at 10° C. and the stirring was continued at roomtemperature for 3 hours. The reaction mixture was diluted with water (24mL) and extracted in ethyl acetate (75 mL), washed with brine and driedover MgSO4. After concentration the crude material obtained was purifiedby silica gel column chromatography to afford compound 4 (510 mg, 50%).

Synthesis of Ethyl(2-^(t)butoxycarbonylamino-3-fluoro-4-((4-bromobenzyl)^(t)butoxycarbonylamino)phenyl)carbamate (5)

To a heavy walled glass tube charged with 4 (0.50 g, 1.3 mmol, 1.00equiv.) was added 5 mL of THF:DCM (1:1) followed by addition of Bocanhydride (0.85 g, 3.9 mmol, 3.0 equiv.). The tube was then sealed andheated to 50° C. for 24 hours. After cooling to room temperature themixture was concentrated and taken up in ethyl acetate, washed withwater and dried over MgSO₄. Concentration of the solution gave a residuethat was purified by silica gel chromatography (hexanes:ethylacetate) togive compound 5 (420 mg, 55%).

Synthesis of Ethyl(2-^(t)butoxycarbonylamino-3-fluoro-4-((4-(1,3,2-dioxoborolan-2-yl)benzyl)^(t)butoxycarbonylamino)phenyl)carbamate (6)

To a 20 mL vial was charged 5 (380 mg, 0.65 mmol), bispinacolatodiboron(198 mg, 0.78 mmol, 1.2 equiv.), potassium acetate (192 mg, 1.95 mmol, 3equiv.) and Pd(dppf)Cl₂.CH₂Cl₂ (23.7 mg, 0.032 mmol, 0.05 equiv.).Dioxane was then added and the reaction stirred at 95° C. for 12 hoursunder nitrogen. The reaction mixture was then concentrated and filteredthrough a pad of silica eluting with 1:1 hexanes:ethylacetate (200 mL).The clear and colorless filtrate was then concentrated and purifiedusing silica gel chromatography (hexanes:ethylacetate) to give compound6 (260 mg, 63%).

To a 20 ml vial was charged 6 (240 mg, 0.38 mmol) and A (232 mg, 0.38mmol, 1 equiv.). 7.6 ml of 1:1 benzene:methanol was then added followedby potassium carbonate (79 mg, 0.57 mmol, 1.5 equiv.). The reactionsolution was stirred for 22 hours after which it was concentrated,re-dissolved in dichloromethane and filtered through a pad of celiteeluting with dichloromethane (40 mL). The filtrate was concentrated andpurified by silica gel chromatography (hexanes:ethyl acetate) to obtaincompound 7 as a yellow solid (230 mg, 58%). NOTE: Compound A shown abovewas synthesized according to published procedure (Lee et. al., Science,2011, 334, 639-642)

¹⁸F (as ¹⁸O water) obtained from PETNET (Woburn, Mass.) was firsttrapped on a QMA Light cartridge (Waters, Milford, Mass.) that waspreviously conditioned with 10 mL of 4 mg/mL KHCO₃ solution followed by10 mL of water. The ¹⁸F trapped was then eluted with 0.5 ml of 2 mg/mLKHCO₃ solution and the cartridge washed with 0.5 mL of 18C6 solution inacetonitrile (26.2 mg/ml) into a 5 mL Wheaton Reacti-Vial. The vial wasthen inserted into a heating block at 110° C. for drying under a streamof nitrogen. An additional 1 ml acetonitrile was used for drying afterwhich a white residue was seen on the walls of the vial. This wasfollowed by an acetone exchange step in which 0.5 ml of acetone wasadded and removed under a constant stream of nitrogen without heating. Aglassy film along the sides and a viscous liquid at the bottom of thevial were obtained at the end of this process (approximately 15 mintotal time). A stir bar was then introduced and the vial quickly cappedwhile being flushed with nitrogen.

Pd(IV)Picoline (10 mg) contained in a sealed nitrogen filled vial, wasdissolved in acetone (0.5-0.6 mL) and added to the above vial containingdried ¹⁸F. This mixture was stirred vigorously for 10 minutes afterwhich the cap was opened and the solution filtered through a pipettecontaining JandaJel™-Polypyridine (20-30 mg) followed by rinsing withadditional 0.5 ml of acetone into a vial containing compound 7 (4-5 mg).This vial was then heated to 85° C. for 10 minutes after which analysisby radio-TLC indicated 37% conversion. The acetone was then evaporatedand 0.5 ml of hexanes:ethyl acetate (1:1) was added. This was thenpassed through a pipette containing silica followed by elution withadditional 1-1.5 ml hexanes:ethyl acetate (1:1). The hexanes:ethylacetate solution was then evaporated to dryness and concentrated HCl(0.5 mL) was added. The vial was then heated to 85° C. for 5 minutesfollowed by reconstitution to 2 ml of 1:1 MeCN:Water followed bypurification on the Semi Prep HPLC (4.6×10 mm Xterra MS C₁₈, 6:4MeCN:Water with 0.1% formic acid; 5 ml/min) to get the desired product.The retention time of 9A matched that for the corresponding ¹⁹Fcompound.

NOTE: Pd(IV)Picoline was synthesized according to published procedure((Lee et. al., Science, 2011, 334, 639-642).

Example 3 Assessment of KCNQ2/3 Channel Activation Activity

The in vitro effects of ezogabine and Compound 1A on cloned KCNQ2/3potassium channels (encoded by the human KCNQ2/3 gene and expressed inHEK293 cells) were evaluated at room temperature using the QPatch HT®(Sophion Bioscience A/S, Denmark), an automatic parallel patch clampsystem. Each test article was evaluated at 0.01, 0.1, 1, 10 and 100 μMwith each concentration tested in at least two cells (n≧2). The durationof exposure to each test article concentration was 5 minutes.

The baseline for each recording was established using a 5-10 minutevehicle application (HBPS+0.3% DMSO). A single test articleconcentration was applied for a period of 5 minutes after the vehicle,followed by a 3 minute application of 30 μM flupirtine. Each recordingended with a supramaximal dose of 30 μM linopirdine. A summary of theresults is shown in Table 4. The % activation was calculated using thefollowing equation by using leak subtracted responses:

$\frac{{vehicle\_ response} - {compound\_ response}}{{vehicle\_ response} - {flupirtine\_ response}}$

TABLE 4 Individual Mean % Data Test KCNQ2/3 Points Article Cone Activa-Standard Standard (% Acti- ID (μM) tion Deviation Error n vation)ezogabine 0.01 6.6 6.4 4.5 2 2.1 11.1 0.1 40.6 11.9 8.4 2 32.2 49.1 194.4 1.1 0.8 2 93.6 95.2 10 132.0 11.8 8.3 2 123.7 140.4 100 104.1 11.56.6 3 93.8 101.9 116.5 Com- 0.01 31.4 6.3 4.5 2 35.9 pound 1A 26.9 0.162.9 31.2 18.0 3 98.9 43.3 46.6 1 125.5 2.9 2.0 2 123.5 127.6 10 119.90.3 0.2 2 119.7 120.1 100 61.9 7.5 5.3 2 56.6 67.3Compounds of the present invention 2A, 3A, and 4A were tested in thisassay at a single concentration (0.1 μM) and were found to be equivalentin activity to ezogabine.

What is claimed:
 1. A compound, which is

or a pharmaceutically acceptable salt or solvate thereof.
 2. Apharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt or solvate thereof and one or morepharmaceutically acceptable carrier or excipient.
 3. A method oftreating a subject suffering from or susceptible to conditionsameliorated by KCNQ2/3 potassium channel opening, comprisingadministering to the subject an effective amount of the compound ofclaim 1 or a pharmaceutically acceptable salt or solvate thereof.
 4. Amethod of treating or preventing a disease or disorder selected fromepilepsy, neurodegenerative disorder, CNS disorder, neurotransmissiondisorder, cognitive disorder, cancer, inflammatory disease, ophthalmicdisease, migraine, bipolar disorder, unipolar depression, anxietydisorder, functional bowel disorder, and tinnitus in a subject in needthereof, comprising administering to the subject an effective amount ofthe compound of claim 1 or a pharmaceutically acceptable salt or solvatethereof.
 5. The method of claim 4, wherein the disease is epilepsy.
 6. Amethod of producing an analgesic effect in a subject in need thereof,comprising administering to the subject an effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt or solvatethereof.